The avermectins are a group of eight naturally occurring macrocyclic lactones notable as outstanding parasiticidals. These compounds, which act as Gamma-aminobutyric acid antagonists, exhibit anthelmintic activity of hitherto unprecedented levels, and yet, very low mammalian toxicity. The applicant will study the total synthesis of the avermectins A1b and A2b. New synthetic methods will be developed to enable the preparation of the natural products via convergent routes. In particular, the stereospecific synthesis of substituted spiroketals from the condensation reaction of 1,3,5-tri(lithio-oxy)-1-methoxy-1,3,5-hexatriene with Sigma-lactones will be explored. New phosphorus ylide reagents will be studied for the construction of the avermectin diene unit. Finally, the cycloaddition reaction of substituted ketones with 2-alkoxy-5-methyl-2,5-cyclohexadiene-carboxylic esters will be crucial for our construction of the southern hexahydrobenzofuran ring system. Our studies should lead to diverse compounds for biological evaluation and thereby the design of better clinically useful compounds.